A Rare Case of Blastic Plasmacytoid Dendritic Cell Neoplasm Occurred in Postchemotherapy of Breast Cancer

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy that arises from plasmacytoid dendritic cells. BPDCN typically presents with skin lesions and may involve peripheral blood, bone marrow, lymph nodes, or extranodal sites. It usually arises de novo, and some BPDCN cases are associated with or develop into myeloid neoplasms. Here, we report a case of a 57-year-old female presenting with cervical lymphadenopathy and skin rashes during the COVID-19 pandemic in 2021 following multiple types of postmastectomy therapy for breast cancer. The patient was ultimately diagnosed with BPCDN by lymph node biopsy. To the best of our knowledge, this is the first case report of BPDCN occurring postchemotherapy of breast cancer.

Te development of various therapy-related myeloid neoplasms (t-MN) following breast cancer chemotherapy has been confrmed [10][11][12]. However, we have not come across any reports specifcally describing BPDCN after chemotherapy of breast cancer. Here, we report a case of 57year-old female presenting with lymphadenopathy on the left and right sides of her neck, skin rashes, pancytopenia, and blasts in the peripheral blood. Te patient was diagnosed with BPDCN six years following mastectomy and chemotherapy for breast cancer. We believe this is the frst case report of BPDCN occurring postchemotherapy of breast cancer.
presented with a palpable 2.0 cm nodule on her right breast. Mammogram taken in July 2015 showed a nodule suspicious for malignancy. Ultrasound showed suspicious regular palpable 1.7 cm mass with adjacent 0.9 cm irregular nodule in the 2 : 30-3 : 00 right breast. Te patient underwent a surgical core biopsy in July 2015, which showed invasive ductal carcinoma, moderately diferentiated (tubule formation score 3/3, nuclear grade score 2/3, and mitoses score 2/3). Te invasive ductal carcinoma was strongly positive for estrogen receptor (ER) (>95%) and progesterone receptor (PR) (>95%). HER-2 by immunohistochemistry was equivocal (score 2+) and negative by fuorescence in situ hybridization (FISH). Te Ki-67 proliferation index was 5-10%. Te patient underwent right mastectomy with axillary sentinel lymph node dissection in September 2015, and the fnal pathology showed invasive ductal carcinoma, moderately-diferentiated (grade 2) (Figure 1(a)), with solid papillary features and necrosis, measuring 3.5 cm in the greatest dimension, with clear surgical margins. It was associated with ductal carcinoma in situ (DCIS) (Figure 1(b)) and lobular carcinoma in situ (LCIS) (Figure 1(c)). Extensive lymphovascular invasion (LVI) and perineural invasion (PNI) were also identifed. One of two right axillary sentinel lymph nodes was positive for micrometastatic carcinoma (Figure 1(d)). Te fnal pathological stage was pT2N1mi with clear surgical margins.
Subsequently, the patient underwent AC chemotherapy with adriamycin and cyclophosphamide, every 2 weeks for 4 cycles between August 2015 and January 2016. Tis was followed by Taxol (paclitaxel) weekly for a total of 12 treatments (last treatment was done in mid-April 2016). She was treated further with endocrine therapy (tamoxifen) from April 2016 to October 2019 and then changed to aromatase inhibitor with anastrozole after menopause.
Te patient was followed up regularly and did not show any complications until May 2021, when she presented with palpable cervical lymphadenopathy and skin lesions. Notably, this also coincided with receiving her second COVID-19 vaccine. Te lymphadenopathy developed 1-2 weeks after she received the second dose of COVID-19 vaccine. Neck ultrasound performed in May 2021 showed multiple mildly enlarged and prominent subcentimeter lymph nodes throughout the neck bilaterally and within both parotid glands; the impression on ultrasound is likely reactive in the setting of recent vaccination.
Te patient was evaluated by an ENT physician who performed a fne needle aspiration on left neck lymph node in June 2021. Te pathology showed a heterogeneous lymphoid population, favoring a reactive lymph node.
Her repeated computed tomography (CT) on neck in June 2021 revealed an extensive lymphadenopathy throughout the neck and mediastinum. Although COVID-19 vaccination can result in reactive lymphadenopathy, this extensive lymphadenopathy bilaterally would be highly atypical and the fndings can be related to malignancy such as lymphoma. Te patient was subsequently hospitalized to our hospital and underwent further work up including lymph node biopsy.

Laboratory Studies and CT Studies
Laboratory analysis revealed mild leukopenia (WBC 3.36 K/ L), anemia (HB 7.8 g/L), and thrombocytopenia (95 K/UL) with an abnormal diferential showing atypical lymphocytes/ blasts 21%, neutrophils 35%, bands 10%, lymphocytes 21%, monocytes 9%, and metamyelocytes 4%. Te peripheral blood smear showed the atypical lymphoid cells to be medium-sized, and with scanty cytoplasm, fne chromatin, and small nucleoli, resembling lymphoid blasts (Figures 2(a) and 2(b)). COVID-19 testing (SARS-CoV-2 NAAT by realtime PCR of nucleic acid amplifcation) and CMV testing were not detected. Cytogenetics showed a normal female karyotype observed in 20 analyzed metaphase cells. No numerical or structural abnormalities of clinical signifcance were found in these cells. FLT3 mutation by PCR is negative for both internal tandem duplication (ITD) and tyrosine kinase domain (TKD). Epstein-Barr Virus (EBV) serology signifed a past infection. HIV testing was negative. CT scan showed bilateral difuse cervical lymphadenopathy along with bilateral intraparotid glands, mediastina, and left axillary lymphadenopathy.

Diagnosis
An excisional lymph node biopsy on the right neck was performed. Te lymph node architecture was completely efaced by a difuse proliferation of medium-sized atypical hematopoietic cells with a scant amount of cytoplasm, a round, oval, cofee-bean shaped, or irregular nuclei with indistinct nucleoli (Figures 3(a) and 3(b)). Mitotic fgures were frequently identifed. By immunohistochemistry, the atypical hematopoietic cells showed immunoreactivity for BCL-2, CD4 (Figure 3 Te morphology and immunostaining profle were diagnostic of blastic plasmacytoid dendritic cell neoplasm (BPDCN), and fow cytometry performed on the peripheral blood later confrmed the diagnosis of BPDCN. Te patient was transferred to an advanced leukemia and lymphoma center for a clinical trial with Tagraxofusp. Later, the patient received a stem cell transplantation, and she is currently in remission.

Discussion
BPDCN is a rare aggressive hematopoietic neoplasm derived from plasmacytoid dendritic precursor cells (type I interferon-producing cells or plasmacytoid monocytes). Since this neoplasm was frst described by Adachi M's group in 1994 [13], BPDCN has been referred to by various names, including agranular CD4+ natural killer (NK) leukemia [14], 2 Case Reports in Hematology CD4+/CD56+ hematodermic neoplasm [2,15], and blastic NK lymphoma [16]. In 2008, the WHO placed this rare neoplasm in the category of AML and related precursor neoplasms [17] following the realization that BPDCN results from the clonal proliferation of immature plasmacytoid dendritic cells (PDC) [18]. In 2016, the WHO classifed BPDCN as a distinct neoplastic entity [1]. In normal situations, the PDCs are an essential part of the innate adaptive immunoresponse [19,20]. Tese cells respond to bacterial and viral infections and other pathogens by producing alpha-interferon; hence, they are also known as alphainterferon producing cells or plasmacytoid monocytes.
Proliferation of the normal PDCs can occur in autoimmune disorders as well [19,20].

Diagnosis and Diferential Diagnosis.
Te diagnosis of BPDCN is based on the clinical manifestation, histology/ morphology, immunohistochemistry, and fow cytometry. Because it shows some similar morphological and immunohistochemical features to other malignant neoplasms, extensive immunohistochemistry, fow cytometry, and/or genetic analysis are essential for a defnite diagnosis of BPDCN. Te diferential diagnosis predominantly includes hematopoietic neoplasms and nonhematopoietic neoplasms. Te former consists mainly of AML with monocytic differentiation, T-lymphoblastic leukemia/lymphoma or early T-cell precursor lymphoblastic leukemia/lymphoma, extranodal NK-T-cell lymphoma, mature T-cell lymphoma, myeloid sarcoma, histiocytic sarcoma, and others. Te latter includes malignant melanoma, poorly-diferentiated carcinoma, and high grade/undiferentiated sarcoma.

Terapy-Related Myeloid Neoplasms and Postchemotherapy of Solid Tumors.
Terapy-related myeloid neoplasms (t-MN) are thought to be the consequence of mutational events induced by cytotoxic therapy. Cytotoxic agents implicated in therapy-related myeloid neoplasm include alkylating agents, ionizing radiation therapy, topoisomerase II inhibitors, and others [1]. Te alkylating agents demonstrated and implicated in t-MN include melphalan, cyclophosphamine, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, decarbazine, procarbazine, carmustine, mitomycin C, thiotepa, lomustine, ifosfamide, and temozolomide [1,11,23]. Tey have been known for many years to induce t-MN. Studies have demonstrated chromosomal deletions involving the 5q and 7q regions, as well as complex karyotypes and mutation or loss p53 commonly present in these patients [24][25][26][27]. Tese chromosomal losses lead to several gene defects that are involved in haematopoiesis and may trigger the progression to t-MN [28,29]. Topoisomerase II inhibitors linked to and implicated in t-MN include etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, and actinomycin [1,11,23]. Topoisomerase II inhibitors hinder DNA topoisomerases. DNA topoisomerases are enzymes critical for cellular function as they regulate DNA winding through removal of knots and tangles [30]. Tey execute important cellular activities such as ensuring DNA stability during replication. Inhibited function can cause cell damage by trapping the enzymes in covalent complexes on the DNA [30]. Te other agents used for the treatment of solid tumors (not implicated here) are antimetabolites and antitubulin agents which include vincristine, vinblastine, vindesine, paclitaxel, and docetaxel [1].
Te most common cohort of t-MN occurs 5-10 years after exposure to alkylating agents and ionizing radiation [1]. Te second t-MN subset accounts for 20-30% of cases, has a shorter latency period of 1-5 years, and is associated with treatment agents that interact with DNA topoisomerase II (e.g., topoisomerase II inhibitors) [1]. Te site of involvement is predominantly peripheral blood and bone marrow. In t-MN patients, about 70% have been treated for a solid tumor and 30% for a hematological neoplasm, with breast cancer making up the largest numbers of cases [31][32][33]. Te development of therapy-related myeloid neoplasm (t-MN) after chemotherapy of breast cancer has been confrmed [31][32][33]. In 20-30% of t-MN cases, the frst manifestation is overt acute leukemia, without a preceding myelodysplastic phase [1].

Is BPDCN COVID-19
Vaccine-Related? COVID-19 vaccines are commonly administered intramuscularly to the arm/deltoid muscle. An association between vaccine administration and the development of ipsilateral axillary and supraclavicular lymphadenopathy has been reported [34,35]. Te incidence of lymphadenopathy varies. One review showed pooled incidence of clinically detected lymphadenopathy after COVID-19 vaccination was 0.4% [35]. A recently published retrospective case series analyzed the mammograms of patients with a history of administration of at least 1 dose of a COVID-19 vaccine within the previous 90 days and identifed 23 cases of axillary adenopathy (3%), which is higher than reported rates of axillary lymphadenopathy in otherwise normal mammography (0.02-0.04%) [34,36]. Te incidence of lymphadenopathy was found to be higher in the frst 2 weeks following the vaccination, and it usually resolves within 3-6 weeks [34][35][36]. If lymphadenopathy persists for more than 6 weeks, or becomes worse, an appropriate management strategy should be taken. In our case, the patient developed multiple enlarged lymph nodes throughout the neck bilaterally, within both parotid glands, and mediastinum 1-2 weeks after the second dose of COVID-19 vaccine. Te possibility that receiving a second dose of the COVID-19 vaccine initiated or aggravated the lymphadenopathy cannot be disproved. However, we do not have solid evidence to suggest that the vaccine directly caused or resulted in lymphadenopathy. Presently, no published literature provides direct evidence to support that COVID-19 can induce hematological malignant neoplasms.

Is BPDCN Terapy-Related or Does It Arise De Novo?
In our case, several interesting phenomena were observed. First, the patient had a history of invasive and metastatic breast cancer, and she received chemotherapy including alkylating agent (cyclophosphamide), topoisomerase II inhibitor (doxorubicin/adriamycin), antitubulin agent (paclitaxel), estrogen receptor antagonist (tamoxifen), and aromatase inhibitors (anastrozole). Second, the patient developed BPDCN six years of postchemotherapy, which falls in the range of about 5-10 years after exposure to alkylating agents [1]. Tird, the involvement is not local or limited to lymph nodes, but is systemic and extensive, including bone marrow, peripheral blood, and multiple lymph nodes (bilateral difuse cervical lymphadenopathy along with bilateral intraparotid glands, mediastina, and left axillary lymphadenopathy). Fourth, the patient had no history of myelodysplastic syndrome or related hematopoietic neoplasms before, except breast carcinoma. Fifth, cytogenetics showed a normal female karyotype without any numerical and structural abnormalities. On the one hand, several related factors observed in our patient's data (presented above) can suggest causality and raise the possibility that BPDCN here may be a therapyrelated occurrence. On the other hand, no direct evidence to support such claim exists. Due to the complexity of possible interactive efects of treatment agents, broad timeline, potential interference of additional unknown factors and random process, and the sheer rarity BPDCN in general, the genuine causes cannot be accurately determined.
In conclusion, we reported what we believe is the only case to date of BPDCN occurring postmastectomy and postchemotherapy of breast cancer. Te absence of similar case reports and complexity of etiology preclude us from making any conclusions regarding potential causality or relationship between breast cancer chemotherapy and BPDCN. However, given that numerous reports identify a link between chemotherapy agents and other types of t-MNs, we cannot entirely dismiss this possibility. While de novo manifestation remains entirely plausible, we would like to encourage medical practitioners to at least consider BPDCN as a potential risk factor of breast cancer chemotherapy, albeit highly rare and unlikely.

Data Availability
Te data used to support the fndings of this study are included within the article.

Conflicts of Interest
Te authors declare that they have no conficts of interest.
Case Reports in Hematology 5